The principal objective of project 5 is to define the cell-mediated immune mechanisms responsible for the development of accelerated graft arteriosclerosis (AGA). One of the central tenets to be tested in this project is that the association of AGA with CsA treatment is due to or exacerbated by the aberrant "autoimmune" recognition of MHC Class II antigens. The "autoreactive" T cells that mediate this chronic inflammatory response are the direct result of CsA treatment which inhibits the clonal deletion of a unique subset of T cells that promiscuously recognize both auto and allo MHC Class Il determinants. This hypothesis is supported by the findings that: 1) AGA is positively correlated with the use of CsA; 2) CsA induced "autoreactive" T cells mediate an inflammatory process consistent with chronic rejection; and 3) "autoreactive" T cells can be detected within he graft during CsA treatment. Moreover, strains of animals that differ in their susceptibility also exhibit a differential effect of CsA on the induction of AGA. The production and localization of this unique autoreactive cell population to the graft promotes the development of AGA due to recognition of MHC Class II determinants upregulated on endothelial cells within the graft. Several factors contribute to the upregulation of MHC Class II determinants and include initial allorecognition and the release of v- interferon, ischemia and infection with cytomegalovirus. The factors also contribute to the development of AGA independent of CsA treatment indicating that other immune mechanisms contribute to this chronic inflammatory process. Therefore, the specific aims of this project are to 1) define the cell-mediated allo and autoimmune mechanisms leading to AG particularly examining the role of CsA induced MHC Class II reactive T cells, 2) dissect the intragraft cellular immune mechanisms responsible for AGA and 3) define the requirements for autoimmune recognition of vascular endothelial cells in AGA in order to develop novel therapeutic strategies. The development of these strategies is based, in part, on the recent demonstration that the autoreactive T cells induced by CsA recognize a peptide from the MHC Class Il invariant chain presented by MHC Class Il determinants. Antibodies to the peptide that block recognition and divalent soluble MHC Class Il antigens complexed to the peptide will be assessed for their efficacy in preventing AGA.